The cells of the oral mucosa are highly sensitive to nutritional de- ficiencies resulting in a number of histological and biochemical changes. It is likely that these changes could increase the susceptibility of this tissue to neoplastic development. Indeed, several lines of evidence suggest that nutritional factors are involved in cancer of the oral cavity, especially, in the absence of the major risk factors, tobacco and alcohol. The significance of this is exemplified by the recent increase in the incidence of non-tobacco and non-alcohol related cancer of the oral cavity, primarily in young people. Our hypothesis is that deficiencies in specific nutrients including iron, riboflavin, vitamin A, vitamin C and beta-carotene play an important role in the etiology of cancer of the oral cavity. Their mechanism of action involves oxidative damage and loss of detoxification capacity in the oral mucosa, resulting in increased susceptibility to carcinogens. To test this hypothesis in humans, we plan to assess the nutritional status of patients with oral cavity cancer or with oral leukoplakia. All subjects will be compared to controls matched for age, sex and smoking and drinking status. A unique aspect of the study will be the biochemical validation of tobacco exposure by plasma cotinine determination and chronic ethanol consumption by acetaldehyde-hemoglobin adduct determination. We also plan to utilize exfoliated buccal mucosal cells in order to assess the nutritional status of the oral mucosa. In addition to the clinical and nutritional measurements, questionnaire data on lifestyle, socio-economics, and dietary habits will be obtained. Finally, the levels of lipid peroxidation and glutathione status will be determined in order to investigate possible mechanisms of action. This study should provide, for the first time, important information on the role of specific nutrients in oral cavity cancer in humans. This information may then be used to design interventions aimed at reducing these risk factors for oral cavity cancer.